The present research plan has been redrafted because an earlier version presented in August 1974 was not funded. It represents a proposal for work which will be initiated should it be funded and a summary of work completed through termination of the project period in December 1975. This research plan embodies proposals to study two models of experimental obesity. These models are: 1) genetically transmitted obesity; and 2) obesity which follows injury to the ventromedial hypothalamus. The information which accrues from these studies should extend our knowledge about obesity to new frontiers which may be useful in developing new strategies and tactics for dealing with the clinical problem of the obese patient, a product of this affluent society. This study is designed to assess three hypotheses for these syndromes. First, whether the genetic abnormality has a cellular basis being present in many (if not all) tissues in genetically obese animals. The second hypothesis is that the apparent multiplicity of cellular defects can be ascribed to the presence of a single circulating substance which acts on many tissues. The third hypothesis is that the entire syndrome might represent an abnormality of the hypothalamic-pituitary axis. The studies of hypothalamic obesity are designed to explore the increased levels of insulin and reduced levels of glucagon which characterize this syndrome. Specifically, we will focus on the afferent and the efferent function of the vagus nerve in controlling the secretion of insulin and glucagon.